This study will evaluate methods to reduce iron overload in patients with severe thalassemia major. This goal will be approached by attempting: (1) to reduce Fe intake utilizing transfused red cells with improved survival prepared by gradient centrifugation and (2) to increase output by intensive chelation therapy. The subjects of the study will be children aged 2 to 22 with severe thalassemia major, who are transfusion-dependent for survival. These patients have been maintained in excellent clinical conditions by a transfusion regimen directed to maintain baseline hemoglobin above 9.5 g/dl. This regimen prevents bone malformation and cardiomegaly and eliminates excessive alimentary Fe absorption; yet it unavoidably results in progressive accumulation of Fe. Preliminary data indicate that prolonged treatment with Desferrioxamine B and 2,3-dihydroxybenzoic acid, a recently developed iron chelator. The efficacy of these therapeutic modalities will be evaluated not only in regard to the iron balance, but also to the cardiological, endocrinological and general clinical improvement. Methods will be developed to separate from normal blood the 50% youngest red cells, which have a better survival. Preliminary studies in the rabbit have indicated that this can be achieved by buoyant density separation on Stractan II (an arabinogalactane polymer of 30,000 daltons). These studies will be extended to other animal species, such as the monkey and dog, in whom red cell life span more closely resembles that of human red cells, which exhibit only minimal random loss. Toxicity and antigenicity studies will also be performed with Stractan II, to assess the safety of red cells isolated on this medium for human use. Other alternative density media for isolation of younger red cells will be tested. It is hoped that by simultaneously reducing Fe input and increasing output with these techniques, it may be possible to avoid the effects of chronic Fe overload in the patients and ultimately prolong their life well into adulthood.